Individual differences in intrinsic cellular radiosensitivity account for at least part of the observed variation in normal tissue responses in radiotherapy patients. This conclusion is based on clinical correlations between early passage fibroblast radiosensitivity and the severity of normal tissue damage in patients. However, normal tissue response to radiation is also influenced by signals of growth, proliferation, and differentiation, which are responses that change with age and physiological conditions. This proposal aims to extend the initial findings of the investigators with additional clinical studies comparing fibroblast radiosensitivity with normal tissue reactions to radiotherapy, to develop alternative or adjuvant non-clonogenic endpoints for in vitro radiation sensitivity measurements, and to test the hypothesis that biological features associated with aging, cellular senescence and radiation-induction of cellular senescence are important for the clinical response of normal tissues to radiotherapy.